In the past several decades, advances have been made in various methodologies which allow the visualization of internal organs and tissue structures using non-invasive techniques. In particular, the development of advanced radiographic techniques such as CT allow for the differentiation of soft tissue structures with density differences as small as 0.5%, whereas with conventional x-ray techniques such differentiation was not possible.
One of the most significant advances in conventional x-ray was the development of water-soluble iodine containing radiographic contrast media. Canada reported the use of an orally ingested contrast media which was used for imaging of the gastrointestinal tract (W. J. Canada (1955) Radiology 64:867-873.) The radio-opacity of the iodine made the gastrointestinal tract lumen appear bright white in the x-ray image. This allowed for better visualization of obstructions and perforations.
Both orally ingested barium sulfate suspensions and water soluble iodine containing contrast media have also been used as positive (high density) contrast media for CT applications. These positive oral contrast agents provide valuable information about the gastrointestinal lumen in which they are localized during imaging. However, their opacity in the CT image can diminish the ability to evaluate wall structures and surrounding tissues and organs. Of particular importance, is the inability to correctly determine gastrointestinal wall thickness as an indicator of possible disease in the presence of a positive contrast agent which obscures wall definitions (Fisher, Radiology (1982) 145:415-418.) Also, when a positive contrast agent is employed, it can obscure the imaging of adjacent calcifications and the ability to carefully evaluate the stomach and duodenum. (Lee et al., eds., Computed Body Tomography with MRI Correlation, Second Edition, Raven Press, New York, Chapter 3, pp. 44-46).
In some cases, the use of positive contrast agents can lead to a false positive diagnosis of pathologic processes, sometimes referred to as pseudotumors (Marks et al., Gastrointestinal Radiology (1980) 5:155-160.) Further problems which arise when using either barium sulfate suspensions or water-soluble iodinated oral contrast agents can be due to the inability of these agents to mix well with the contents of the gastrointestinal tract thus giving rise to a heterogeneous opacification and artifacts in the CT image (Garret et al., Radiology (1984) 153:545-546).
In the absence of an orally administered contrast agent, imaging of the upper abdomen can also be affected by the contents of the gastrointestinal tract, which may produce imaging artifacts. If the imaging densities of the heterogeneous gastrointestinal contents are similar to that of the surrounding tissues, the visualization of such tissues and organs proximal thereto can be obscured. In addition, the uneven distension of the colon due to the presence of normal intestinal contents (gas and stool) can further interfere with imaging.
One way in which to overcome the difficulties associated with positive contrast agents or the absence of a contrast agent is to introduce a low density contrast agent into the gastrointestinal tract. Alger has reported that for upper gastrointestinal imaging, water in combination with intravenous glucagon (an anti-peristaltic agent) can be given to patients prior to CT examination to enhance the visualization of the area (Oral presentation of American Roentgen Ray Society Meeting summarized in Diagnostic Imaging, January 1994, page 22.) However, the use of water has been reported to lead to the production of imaging artifacts (Baldwin, Radiology (1978) 128:827-828.) Additionally, without concomitant intravenous administration of an anti-peristaltic agent such as glucagon, the rapid gastric emptying of water would not allow for full distention of the stomach.
Many investigators have described the use of low-density contrast media for CT examinations. The radiodensity of matter is often expressed in terms of its Hounsfield Units (HU), which is a measure of the relative absorption of CT x-rays by matter. Dense bone has a density of 1000 HU, whereas water has a density of 0 HU and air has a value of -1000 HU. In general, the term "low-density" is used to refer to contrast media with a low or negative HU, i.e. less than about 100 HU, preferably less than 10 HU, and most preferably less than 0 HU.
Baldwin reported the administration of low density oily contrast media for CT of the pancreas. However, because of associated cramps and diarrhea, a dose of 4 ounces was suggested, which would not be enough to sufficiently fill the stomach and/or gastrointestinal lumen. (Baldwin, Radiology (1978) 128:827-828.)
Raptopoulos et al., has described the use of a corn oil emulsion as a low density contrast agent (Radiology (1987) 164 (3) :653-656. At a dosage amount of between 200-500cc, 18% of the patient group complained of nausea, vomiting, cramps or diarrhea. Another disadvantage with the use of polyunsaturated fat-based low density contrast agents is their absorption by the gastrointestinal tract (Raptopoulos, Investigative Radiology (1986) 21(11):847-850.) In European Patent Application 0 245 019A2, Raptopoulos has described the use of oil-in-water emulsions suspended in an aqueous isotonic solution which demonstrate improved homeostasis.
A similar approach has been described in PCT WO92/17514. Therein, microspheres are prepared from biocompatible synthetic polymers to contain internal cavities filled with gas. Because of the presence of gas, these microspheres have a lower radiodensity than water. These microspheres are then suspended in an aqueous medium at concentrations that generate a contrast medium with a HU less than -30. The preparation of such microspheres necessitates multi-step methodologies involving volatile liquids. In addition, the microspheres in the preferred size ranges would not be stable upon storage in aqueous solution thus requiring dry storage and mixing with a carrier liquid prior to use.
The present invention describes a method of CT imaging of the abdominal region using low density contrast agents consisting of aqueous solutions of biocompatible materials which are stable, have a density (in Hounsfield Units) essentially the same or less than that of water, and are capable of filing and distending the stomach.